機会の不平等: ネパールを事例とした実証分析

早大学位記番号:新8376早稲田大

Considering the role of presence and absence in space constructions: ethnography as methodology in human geography

In this article, we discuss methodological issues and problems in researching relational space. We argue that despite all innovations after recent spatial turns, research on space is often still marked by what we call ‘presentism’ and ‘concretism’. Instead, we seek to show how spatial encounters today are more and more marked and shaped by different absences. Using some insights from the poststructuralist take on assemblages we argue that any spatial method to understand spatial complexity is incomplete if the role of absences in shaping spatial presences and spatial encounters is left unconsidered. Addressing ques-tions of methodology and methods we vote for the ethnographic approach which, to us, has the strongest potential to undertake spatial research sensitive to the problem of present absences, i.e. that the complexity of places is often shaped by absent spatial events

Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

Simple Summary AML is a genetically heterogeneous disease with a median age of diagnosis between 60 and 70 years. Thus, many AML patients are not eligible for intensive chemotherapy. Often, the disease is accompanied by a poor prognosis due to high-risk genetic features or due to antecedent hematologic disorders (e.g., myelodysplastic syndrome). Therefore, AML treatment remains a challenge; even after intensive chemotherapy and allogeneic stem cell transplantation (alloHSCT), AML relapses are regularly observed. Thus, new concepts of AML therapy, considering tailored treatment approaches after comprehensive molecular diagnostic or implementing new immunotherapeutic strategies, are urgently needed. This review provides a detailed overview of recent developments and current promising concepts to improve the treatment and the outcome of AML patients. Abstract Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients

Intercalibrating the national classifications of ecological status for very large rivers in Europe: Biological Quality Element: Benthic invertebrates

The European Water Framework Directive (WFD) requires the national classifications of good ecological status to be harmonised through an intercalibration exercise. In this exercise, significant differences in status classification among Member States are harmonized by comparing and, if necessary, adjusting the good status boundaries of the national assessment methods. Intercalibration is performed for rivers, lakes, coastal and transitional waters, focusing on selected types of water bodies (intercalibration types), anthropogenic pressures and Biological Quality Elements. Intercalibration exercises were carried out in Geographical Intercalibration Groups - larger geographical units including Member States with similar water body types - and followed the procedure described in the WFD Common Implementation Strategy Guidance document on the intercalibration process (European Commission, 2011). The Technical reports are organized in volumes according to the water category (rivers, lakes, coastal and transitional waters), Biological Quality Element and Geographical Intercalibration group. This volume addresses the intercalibration of the Very large river Benthic invertebrate ecological assessment methods. Nineteen countries (Austria, Belgium (Flanders), Bulgaria, Croatia, Czech Republic, Estonia, Finland, Germany, Hungary, Latvia, Lithuania, the Netherlands, Norway, Poland, Romania, Slovakia, Slovenia, Spain and Sweden) participated in the intercalibration exercise and harmonised their benthic invertebrate assessment systems. The results were approved by the WG ECOSTAT and included in the EC Decision on intercalibration (European Commission, 2018).JRC.D.2-Water and Marine Resource

Generation and characterization of a mitotane-resistant adrenocortical cell line

Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo

Numerical simulation of dual-phase steel based on real and virtual three-dimensional microstructures

Dual-phase steel shows a strong connection between its microstructure and its mechanical properties. This structure–property correlation is caused by the composition of the microstructure of a soft ferritic matrix with embedded hard martensite areas, leading to a simultaneous increase in strength and ductility. As a result, dual-phase steels are widely used especially for strength-relevant and energy-absorbing sheet metal structures. However, their use as heavy plate steel is also desirable. Therefore, a better understanding of the structure–property correlation is of great interest. Microstructure-based simulation is essential for a realistic simulation of the mechanical properties of dual-phase steel. This paper describes the entire process route of such a simulation, from the extraction of the microstructure by 3D tomography and the determination of the properties of the individual phases by nanoindentation, to the implementation of a simulation model and its validation by experiments. In addition to simulations based on real microstructures, simulations based on virtual microstructures are also of great importance. Thus, a model for the generation of virtual microstructures is presented, allowing for the same statistical properties as real microstructures. With the help of these structures and the aforementioned simulation model, it is then possible to predict the mechanical properties of a dual-phase steel, whose three-dimensional (3D) microstructure is not yet known with high accuracy. This will enable future investigations of new dual-phase steel microstructures within a virtual laboratory even before their production

RVE-size Estimation and Efficient Microstructure-based Simulation of Dual-Phase Steel

Dual-phase steel shows a pronounced structure-property correlation, caused by its internal structure consisting of asoft ferrite matrix and embedded hard martensite regions. Due to its high strength combined with high ductility, dual-phasesteel is particularly suitable for energy-absorbing and strength-relevant sheet metal applications, but its use as heavy plate isalso desirable. Due to the complex microstructure, microstructure-based simulation is essential for a realistic simulation of themechanical properties of dual-phase steel. This paper describes two important points for the microstructure-based simulation ofdual-phase steel. First a method for the straightforward experimental estimation of the RVE size based on hardness measurementsprior to tomography preparation is presented and evaluated. Secondly, a method for the efficient meshing of these microstructures,based on material definition at the integration points of a finite element model, is developed

Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance

OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization. AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA. METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography–tandem mass spectrometry was performed to assess differential protein expression. RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment. CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies

Learning-based adaption of robotic friction models

In the Fourth Industrial Revolution, wherein artificial intelligence and the automation of machines occupy a central role, the deployment of robots is indispensable. However, the manufacturing process using robots, especially in collaboration with humans, is highly intricate. In particular, modeling the friction torque in robotic joints is a longstanding problem due to the lack of a good mathematical description. This motivates the usage of data-driven methods in recent works. However, model-based and data-driven models often exhibit limitations in their ability to generalize beyond the specific dynamics they were trained on, as we demonstrate in this paper. To address this challenge, we introduce a novel approach based on residual learning, which aims to adapt an existing friction model to new dynamics using as little data as possible. We validate our approach by training a base neural network on a symmetric friction data set to learn an accurate relation between the velocity and the friction torque. Subsequently, to adapt to more complex asymmetric settings, we train a second network on a small dataset, focusing on predicting the residual of the initial network's output. By combining the output of both networks in a suitable manner, our proposed estimator outperforms the conventional model-based approach and the base neural network significantly. Furthermore, we evaluate our method on trajectories involving external loads and still observe a substantial improvement, approximately 60-70\%, over the conventional approach. Our method does not rely on data with external load during training, eliminating the need for external torque sensors. This demonstrates the generalization capability of our approach, even with a small amount of data-only 43 seconds of a robot movement-enabling adaptation to diverse scenarios based on prior knowledge about friction in different settings